Identification of Genomic Alterations Acquired During Treatment With EGFR-TKIs in Non-small Cell Lung Cancer

Anticancer Res. 2019 Feb;39(2):671-677. doi: 10.21873/anticanres.13162.

Abstract

Background/aim: Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually develop resistance to these drugs. Although various mechanisms of such resistance have been identified, the mechanism in many cases remains unknown.

Materials and methods: Whole-exome sequencing was performed for tumor tissue from 15 patients with NSCLC who developed EGFR-TKI resistance. Tumor specimens obtained before EGFR-TKI treatment were also analyzed for four patients and normal white blood cell samples for six patients in order to detect genomic alterations that occurred during treatment.

Results: The mutational signature and mutational load acquired during EGFR-TKI treatment varied among patients, with common EGFR-TKI resistance mechanisms including the T790M secondary mutation of EGFR and MET amplification being acquired together with many other genomic alterations. Our results provide insight into the mutational landscape acquired during the development of EGFR-TKI resistance in NSCLC.

Keywords: EGFR-TKI; Non-small cell lung cancer; drug resistance; exome sequencing; genomic mutation.

MeSH terms

  • Aged
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors
  • Exome
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Male
  • Middle Aged
  • Mutation
  • Polymorphism, Single Nucleotide
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors